The renin-angiotensin-aldosterone system (RAAS) plays a critical role in renal physiology. Inhibitors of angiotensin-converting enzyme (ACE) or angiotensin receptor blockers (ARB) are the mainstay in the clinical management of hypertension and renal disorders such as CKD. These treatments are thought to work in large part by reducing aldosterone levels. Despite initial success of ACE inhibition or ARB therapy to reduce aldosterone, in 30-40% of patients, aldosterone is eventually found to return to pretreatment levels, thus severely limiting the long term therapeutic effectiveness. The clinical significance of this “aldosterone breakthrough” is increasingly recognized and several approaches to combat aldosterone escape are being considered. The mineralocorticoid aldosterone has long been known as a key hormone that regulates electrolyte homeostasis, fluid volume and blood pressure. Aldosterone acts through the mineralocorticoid receptor (MR) in the distal nephrons of the kidney to control sodium re-absorption and potassium excretion. In patients with chronic renal disease, plasma aldosterone levels are usually found to be elevated and to correlate with proteinuria. Aldosterone is thought to directly accelerate renal damage by sustaining cell growth, inflammation and fibrosis.
One in ten American adults have some level of chronic kidney disease (CKD), which amounts to more than 20 million US citizens. CKD occurs in both diabetic and non-diabetic nephropathies and is characterized by increasing proteinuria, declining functional nephron mass and a concomitant decline in renal function (glomerular filtration rate (GRF)<60 ml/min). It is estimated that 20-40% of diabetes patients progress to some form of CKD. In 2004, approximately 8 million people in the US were diagnosed with a glomerular filtration rate <60 ml/min. CKD often transitions to end-stage renal disease, a life-threatening condition requiring renal replacement therapy. The number of patients reaching end-stage renal disease has been increasing at an average of 7% per year over the last 10 years. Worldwide, approximately 1.1 million patients are on renal replacement therapy and this number is expected to exceed 2 million in 10 years, with 0.5 million from the US. Many people will die as a result of renal failure if renal replacement therapy is not provided. The annual mortality rate is 20% for patients on dialysis who are waiting for renal transplantation. The combined cost of dialysis and kidney transplantation is estimated to exceed $1 trillion. At present, there is no treatment reverses the course of CKD. Many patients with kidney disease benefit from antihypertensive therapy with inhibitors of angiotensin converting enzyme (ACE) or angiotensin receptor blockers (ARBs). These drugs are usually given in concert with diuretics. However, despite initial success of ACE inhibition or ARB therapy, their long term therapeutic effectiveness is often limited. There continues to be a great unmet medical need for therapies that can complement the current pharmaceutical armamentarium by slowing disease progression, reversing symptoms and delaying or preventing the need for renal replacement therapy. There is also a need for compounds that can prevent the development of fibrosis.